Mamola's first 500cc motorcycle Grand Prix race was in Sweden in 1979, riding a Yamaha. His first victory in the 500cc class was at Belgium in 1980. He went on to win a total of 13 Grands Prix, and finished second in the championship four times: in 1980, 1981, 1984 and 1987. During his Grand Prix career he rode for Yamaha, Suzuki, Honda and Cagiva.
Mamola was also well-known for being a real crowd pleaser. For example, at the Dutch TT he crashed his bike during warm-up, only to return to the pits to get his spare bike, wheelying and showing off to the crowd during the main race. Another memorable moment occurred at the 1986 French GP while trailing race leader Eddie Lawson, who was too far ahead to catch: Mamola had built up a healthy lead over third place rider, Christian Sarron, and decided to pull an endo on the run-off area at the beginning of the pit straight before rejoining the race. The stunt went unnoticed by track marshals who were mere feet away but it was captured on film by photographer Don Morley. The following weekend, Morely presented Mamola with the photograph, who was thrilled it was caught on film, but Yamaha team manager, Kenny Roberts, was not. Roberts fired Mamola on the spot but eventually relented and reinstated him . After leaving the Roberts team, Mamola signed with Cagiva to help them develop their GP500 race bike. He stayed with the Italian team for three years, but lack of funds hampered the teams success. After sitting out the 1991 season, he returned in 1992 for one last year on a privately supported Yamaha. Mamola currently works as a television commentator for MotoGP races on the Eurosport network. He has maintained his crowd pleasing manner, often wearing humorous wigs on camera during interviews with riders. He was inducted into the AMA Motorcycle Hall of Fame in 2000.